It is known that caffeine can affect cell proliferation in vitro and this research examines the effect of dietary caffeine on the colonic epithelium. Subjects are given a well-controlled diet [weight maintaining, metabolic (high fat, low fiber)], with caffeine administered as an independent variable. After a 1-wk baseline, control subjects receive 1 cup of decaffeinated coffee/day and caffeine subjects receive 1 cup of decaffeinated coffee & caffeine (5 mg/kg body wt)/day for 2 wks. Assessment of colonic epithelium, caffeine, and Ki-ras oncogene mutations are performed using endoscopic biopsy (by flexible sigmoidoscopy), blood, and stool samples. Colon cancer is a common human malignancy. Specific dietary components are implicated in its pathogenesis. Caffeine, a common dietary constituent, is known to circumvent cell cycle checkpoints in cultured cells and in yeast. Human tissue culture cells develop gross structural and genetic abnormalities when exposed to caffeine along with agents that cause DNA damage (alkylating agents or ionizing radiation). It is thought that these defects occur because caffeine disrupts physiologic cell cycle checkpoints that delay cell cycle progression until DNA damage is completely repaired. Our hypothesis is that, by mechanisms similar to those observed in vitro, dietary intake of caffeine can affect colonic epithelial cells in vivo. Once a sufficient subject population is studied and laboratory and statistical analyses are completed, we will be able to determine the effects of caffeine on the extent of apoptosis and cell proliferation in the colonic mucosa. In addition, the effects of caffeine on other potential biomarkers for colorectal cancer risk, such as the expression of certain tumor suppressor genes and oncogenes, can be determined. Once these initial analyses are accomplished, additional studies can be undertaken to determine the dose of caffeine which has the greatest effect on the colon mucosa.